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“Alcohol damages DNA of unborn children beyond repair,” The Independent reported today. The newspaper says that “scientists have identified the precise molecular mechanism” through which this damage happens.

Excessive drinking while pregnant is known to cause foetal alcohol syndrome, which can cause life-long learning disabilities, behavioural problems and sometimes physical abnormalities in affected babies. The researchers say that their current study provides a potential biological link between DNA damage and this syndrome.

The study examined the impact of various types of alcohol exposure on mice that were engineered to lack either one or two genes that are involved in the body’s ability to successfully process alcohol and repair DNA damage. These were the Aldh2 gene, involved in breaking down a toxic chemical called acetaldehyde that is formed from alcohol in the body, and the Fancd2 gene, which is involved in repairing damaged DNA. Foetal mice lacking these genes were highly sensitive to alcohol exposure in the womb, showing a reduced rate of survival and an increased rate of severe brain defects.

These results suggest that acetaldehyde-related DNA damage could play a role in the development of foetal alcohol syndrome. However, as they are based on mice lacking two important genes that help protect the body from the toxic effects of alcohol, these results may not directly represent the way that foetal alcohol syndrome occurs in humans, as humans generally have working copies of these genes. Further research will be needed to determine the role that DNA damage plays in this syndrome in humans.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and funded by the Children’s Leukaemia Trust and Fanconi Anaemia Research Fund.

The study was published in the peer-reviewed scientific journal Nature.

The findings of this study were generally reported accurately in the media, although The Independent reported that scientists had identified how alcohol induces DNA damage, saying that they had discovered “the precise molecular mechanism leading to the breakdown of the body’s natural defences”. While this study did find that alcohol increased the risk of foetal damage, this was in genetically engineered mice lacking two key genes that protect the cells from DNA damage from alcohol. Given these important genetic changes and the fact that this was a mouse study, it isn’t possible to say as yet whether DNA damage is solely responsible for causing foetal alcohol syndrome in humans, who would normally have functioning copies of these two genes.

What kind of research was this?

This was a laboratory-based study that included experiments in live mice, some of which had been genetically engineered. Previous research has confirmed that cells exhibit DNA damage when exposed to a specific compound called acetaldehyde, which is formed when the body processes alcohol. There are multiple enzymes responsible for the elimination of accumulated acetaldehydes, and researchers investigated the role of a particular set of genes in the process of protecting the body from the toxic effects of acetaldehyde build-up.

In this study the researchers looked at two genes, the first of which (Aldh2 ) is essential for the breakdown of acetaldehyde, and the second of which (Fancd2 ) has, when absent, been linked to cells’ sensitivity to the toxic effects of acetaldehyde. They sought to determine the effect of alcohol on the development of birth defects in mice that did not posses either of these two key genes, and therefore could not make the proteins for which the genes contain the instructions for producing.

This type of animal study allows researchers to study the role that specific genes play in different processes in the body. However, while animal models are useful for exploring theories and biological mechanisms, they do not always reflect what happens in humans; the way these genes work in mice may differ from the way they work in humans.

What did the research involve?

In the first phase of the study, researchers looked at the role of the Aldh2 gene (which produces an enzyme for breaking down acetaldehyde) and how it affected the survival of foetal mice which had been genetically engineered to lack the Fancd2 gene that is involved in acetaldehyde sensitivity. The aim of this phase was to examine whether foetal mice could survive when lacking these two mechanisms for protecting against the toxic effects of acetaldehyde, as this compound is not just associated with alcohol but other processes as well.

They next looked at whether or not the toxic effects of acetaldehyde were enough, on their own, to cause foetal death or developmental defects. To do this, pregnant mice carrying foetuses lacking the Aldh2 gene and the Fancd2 gene were given a dose of alcohol, and the proportion of the surviving foetal mice that lacked these genes was determined. This was compared to pregnant control mice which were given a dose of saline instead of alcohol. The aim of this phase was to examine whether exposure to alcohol altered survival in foetal mice which lacked the two genes. Differences in the presence of developmental defects were also measured.

In humans, mutations in the Fancd2 gene and other related genes involved in DNA repair cause a disease called Fanconi anaemia, which is characterised by problems in producing blood cells. Additionally, researchers say that previous research has shown that abusing alcohol is associated with the disruption of blood cell production. Based on this, researchers next looked at the effects alcohol had on the generation of blood cells in mice which did not have the Aldh2 and Fancd2 genes. They hypothesised that alcohol exposure would result in an accumulation of acetaldehyde, which would in turn disrupt the mice’s ability to produce blood cells. To do this, researchers regularly added alcohol to the mice’s drinking water and tested their levels of various blood constituents.

Lastly, the researchers examined the health of mice which lacked both the Aldh2 and the Fancd2 genes, but were not exposed to alcohol.

What were the basic results?

The researchers found that the survival of foetal mice that lacked Fancd2 was dependent on either the mother or the pup having the gene Aldh2 . That is, if a pup was genetically predisposed to sensitivity to acetaldehyde, either the mother or the pup had to be able to naturally break down acetaldehyde and prevent it from accumulating in order to for the pup to survive.

The researchers examined the impact of in utero (in the womb) alcohol exposure on foetal death and developmental defects. They found that:

If pregnant mice carrying foetuses that lacked the Aldh2 gene and the Fancd2 gene were given alcohol, this reduced the proportion of foetal mice that survived to birth.

After alcohol exposure about 43% of the surviving foetal mice that lacked both genes exhibited eye abnormalities. This was higher than the rate in foetal mice that lacked both genes but were not exposed to alcohol (20%).

After exposure to alcohol, about 29% of the surviving foetal mice that did not have either gene had a specific type of severe brain abnormality. These problems were not found in the foetal mice which lacked these genes but were not exposed to alcohol.

The researchers also identified problems in blood cell production in the mice lacking these genes that were continuously exposed to alcohol in their drinking water.

When investigating the health of mice with neither gene but which were not exposed to alcohol in the womb, researchers found that:

The pups had subtle developmental defects, but initially appeared to be generally healthy.

Within three to six months, many of the pups developed illnesses with symptoms such as rapid weight loss and lethargy.

After death, the majority of these sick mice were found to have large cancerous masses in multiple organs.

How did the researchers interpret the results?

The researchers concluded that foetal mice which lacked both Aldh2 and Fancd2 are extremely sensitive to alcohol exposure in the womb, and alcohol exposure after birth in these mice is very toxic to bone marrow cells. They say that acetaldehyde-driven DNA damage may contribute to the development of foetal alcohol syndrome in humans.

They also suggest that their research raises possibilities for new therapeutic approaches to treat people with Fanconi anaemia, a disease caused by mutations in the human Fancd2 gene and other related DNA-repairing genes. Such approaches could target aldehyde chemicals in order to prevent their build-up and toxic effects.

Conclusion

This mouse study has identified a potential pathway by which alcohol, or more specifically, by-products of alcohol metabolism, can damage DNA and lead to developmental defects. It presents evidence that the chemical acetaldehyde which is formed by the body from alcohol may drive this DNA damage, and that its breakdown limits this damage. It also identifies a key DNA repair gene which helps to fix this damage.

Excessive drinking while pregnant is known to cause foetal alcohol syndrome, the effects of which can include learning disabilities and other behavioural problems, as well as physical abnormalities. It is possible that acetaldehyde-related DNA damage could be playing a role in the development of this syndrome. However, it is important to bear in mind that these results come from mice lacking two important genes that help protect the body from the toxic effects of alcohol. As most people have working copies of these genes, these results may not be directly representative of foetal alcohol syndrome in humans.

That said, this research has identified several clues that might help us understand the effects of alcohol on the body and on developing foetuses. These clues will now need to be investigated through further research, particularly through studies addressing the role that DNA damage may play in foetal alcohol syndrome.